Autoimmune disease is usually treated using general immunosuppressants. But this non-targeted therapy leaves the body more susceptible to infection and other life-threatening diseases.

Now, scientists at Boston Children’s Hospital, the Massachusetts Institute of Technology (MIT) and the Whitehead Institute for Biomedical Research think they may have found a targeted way to protect the body from autoimmune disease. Their approach, published in Proceedings of the National Academy of Sciences, uses transfusions of engineered red blood cells to re-train the immune system. Early experiments in mice have already shown that the approach can prevent — and even reverse — clinical signs of two autoimmune diseases: a multiple-sclerosis (MS)-like condition and Type 1 diabetes.

Understanding what triggers the immune system

The immune system goes into attack mode when it detects the presence of antigens, which are proteins or other substances it identifies as foreign and potentially harmful. In autoimmune disease, the body’s own proteins are misinterpreted as foreign. These so-called “autoantigens” cause the immune system to attack the body’s own cells.

Red blood cells, however, are pretty special in their ability to evade immune attack. When they become too old to function properly anymore, they signal this by displaying certain proteins. Macrophages, a type of phagocyte cell, detect these proteins and destroy the aged red blood cells. Usually, macrophage activity triggers an immune response. But in the case of red blood cells, this doesn’t happen.

Phagocytes detect foreign proteins, located on the surface of pathogens or other harmful substances, which triggers an immune response. But in autoimmune disease, proteins on the surface of normal cells are incorrectly interpreted as foreign and the immune system attacks the body’s own cells.

Re-training the immune response

“Under normal conditions, once red blood cells have run their course, they are destroyed by the body,” says Hidde Ploegh, PhD, a co-corresponding author on the new study. He began the work at the Whitehead Institute and has since continued it as a newly-appointed investigator in the Program of Cellular and Molecular Medicine (PCMM) at Boston Children’s. “Since this process doesn’t trigger an immune response, we wondered if we could use engineered red blood cells to train the immune system to ignore specific antigens.”

As part of a long-standing collaboration, Ploegh’s lab teamed up with the lab of Harvey Lodish, PhD, who is a founding member of the Whitehead Institute, and an MIT faculty member with expertise in red blood cells. Lodish is also a member of the Board of Trustees at Boston Children’s.

The team of scientists hypothesized that attaching fragments of autoantigens to red blood cells could train the immune system to interpret them as being part of red blood cells. Therefore, these autoantigens could exist peacefully elsewhere in the body, without being subjected to immune attack.

Protecting against autoimmune disease

To induce immune tolerance, the multi-institutional team used an enzyme, called sortase, to link fragments of disease-relevant autoantigens to the red blood cells.

“By attaching these payloads to red blood cells, we hoped to silence the immune response against them,” says Ploegh. “In exploring a mouse model of an MS-like condition, we attached a major central nervous system protein to red blood cells, and then administered these engineered cells by performing a blood transfusion. This approach not only protected mice from developing MS, but it was even possible to reverse early clinical signs of the condition.”

In multiple sclerosis, the protective myelin sheaths of nerve cells in the brain and spinal cord are broken down by the immune system. These spinal cord sections show infiltration of immune cells (top, stained black), which attack the myelin sheaths and cause demyelination (below). Demyelination disrupts nerve activity and results in neurological problems. But, promisingly, a transfusion of engineered red blood cells was able to prevent a multiple-sclerosis-like condition in mice.

“Then, we tested this strategy in mice that were genetically predisposed to develop Type 1 diabetes,” says Novalia Pishesha, an MIT graduate researcher who is co-advised by Ploegh and Lodish. “We linked red blood cells to fragments of insulin that, in diabetes-prone mice, activate autoimmune destruction of the insulin-producing pancreatic cells.”

A transfusion of the engineered red blood cells allowed 80 percent of mice to maintain normal blood glucose levels. In contrast, all untreated mice became diabetic.

Making the jump to humans

“Given the broad acceptance and safety profile of red blood cell transfusions, this antigen-specific tolerance strategy promises a lack of adverse effects,” the team states in their PNAS paper.

Next, the team plans to investigate other therapeutic uses for engineered red blood cells.

In people who lack the ability to make certain enzymes, such as crucial blood clotting factors or lysosomal enzymes, an immune response against therapeutic proteins becomes a dose-limiting complication that hampers their treatment. By administering transfusions of red blood cells linked to antigens for the appropriate therapeutic proteins, this strategy could one day improve enzyme replacement therapy.

Although promising, this work must make the crucial leap from mice to humans if it will ever have any real clinical impact.

“This transition, unfortunately, is where much exciting science bites the dust,” cautions Ploegh. “These successful therapies in mice may not directly translate to humans.”

“But,” Ploegh continues, “now that we know immune tolerance can be induced in certain settings, we must begin the work of finding out the underlying cellular and molecular mechanisms.”

Such information could lead to targeted, red-blood-cell-based immune therapies for people.